Multiple sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons’ myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to autoantigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14⁺ monocytes, mature dendritic cells, and vitamin D₃–tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HDs). Using multiomics, we identified a switch in these cell types toward proinflammatory features characterized by alterations in the aryl hydrocarbon receptor (AhR) and NF-κB pathways. MS patient–derived VitD3-tolDCs showed reduced tolerogenic properties compared with those from HDs, which were fully restored through direct AhR agonism and by use of in vivo or in vitro dimethyl fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS.

中文翻译：

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靶向芳烃受体在功能上恢复来自多发性硬化症患者的致耐受性树突状细胞


多发性硬化症 （MS） 是一种慢性疾病，其特征是自身反应性免疫反应失调，损害神经元的髓鞘，导致进行性残疾。主要的治疗选择是免疫抑制剂，可抑制致病性抗髓鞘反应，但会抑制免疫系统。抗原特异性单核细胞衍生的自体耐耐受性树突状细胞 （tolDC） 提供了替代治疗方法，可在不引起全身免疫抑制的情况下恢复对自身抗原的耐受性。然而，MS 中的免疫失调可能会影响用作该细胞疗法起始材料的单核细胞的特性。在这里，我们表征了来自活动性、未接受过治疗的 MS 患者和健康供体 （HD） 的 CD14 ⁺ 单核细胞、成熟的树突状细胞和维生素 D 3-tolDC （VitD3-tolDC）。使用多组学，我们确定了这些细胞类型向促炎特征的转变，其特征是芳烃受体 （AhR） 和 NF-κB 通路的改变。与 HD 相比，MS 患者来源的 VitD3-tolDC 显示出耐受性降低，而 HD 则通过直接 AhR 激动作用和使用体内或体外富马酸二甲酯 （DMF） 补充剂完全恢复。此外，在实验性自身免疫性脑脊髓炎小鼠模型中，DMF 和 VitD3-tolDCs 的联合治疗在降低小鼠临床评分方面比单药治疗更有效。我们建议 DMF 和 VitD3-tolDCs 的联合治疗在治疗 MS 方面具有增强的潜力。